Transient receptor potential (TRP) channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types. One TRP channel protein of particular interest is the vanilloid receptor 1 (TRPV1 or VR1), a non-selective Ca+2 channel that is the molecular target of vanilloid compounds (e.g., capsaicin and resiniferatoxin). Such vanilloid compounds are known to selectively depolarize nociceptors, specialized primary afferent neurons involved in the signaling pathway that leads to the sensation of pain. TRPV1 is activated by a diverse range of stimuli, including vanilloids, membrane depolarization, heat, stretch, low pH, inflammatory mediators (e.g., lipoxygenase metabolites), and endocannabinoid compounds. Because heightened activity of nociceptors contributes to unwanted pain, inflammatory conditions, thermoregulation, and control of smooth muscle tone and reflexes in mammals, modulation of signaling in this pathway is important in treatment and prophylaxis of various clinical syndromes (Caterina, M. J., Pain 2003, 105(1-2), 5-9; Caterina, M. J. et. al., Annu. Rev. Neurosci. 2001, 24, 487-517; Tominaga, M. et. al., J. Neurobiol. 2004, 61, 3-12; Voets, T. et. al., Nature 2004, 430, 748-754).
Because of TRPV1's connection with the sensory nervous system, TRPV1 agonists and antagonists may be therapeutically useful in the treatment or prophylaxis of disease states, disorders, and conditions mediated by TRPV1 activity, such as: i) pain (e.g., acute, chronic, inflammatory, or neuropathic pain); ii) itch (Kim et al., Neurosci. Lett. 2004, 361, 159) and various inflammatory disorders (Stucky, C. L. et. al., Neuroscience 1998, 84, 1257; Moore, B. A. et. al., Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 282, G1045; Kwak, J. Y. et. al., Neuroscience 1998, 86, 619; Morris, V. H. et. al., Pain 1997, 71, 179; Greiff, L. et. al., Thorax 1995, 50, 225); iii) inner ear disorders (Balaban, C. D. et al., Hear. Res. 2003, 175, 165-70; Zheng, J. et al., J. Neurophys. 2003, 90, 444-55); iv) fever and other disorders or symptoms affected by thermoregulation (Jancso-Gabor et al., J. Physiol. 1970, 206, 495; Swanson et al., J. Med. Chem. 48, 1857; Iida et al., Neurosci. Lett. 2005, 378, 28); v) tracheobronchial and diaphragmatic dysfunction; and vi) gastrointestinal and urinary tract disorders (Lazzeri, M. et al., Eur. Urology 200, 792-798; Apostolidis, A. et. al., Urology 2005, 65, 400-405). Additionally, TRPV1 modulators may be therapeutically useful in the treatment or prophylaxis of anxiety (Marsch, R. et al., J. Neurosci. 2007, 27(4), 832-839); eye-related disorders (such as glaucoma, vision loss, and increased intraocular pressure) (Calkins, D. J. et al., Abstract from ARVO 2006 Annual Meeting, Program #1557, Poster #B93); baldness (e.g., by stimulating hair growth) (Bodo, E. et al., Am. J. Pathol. 2005, 166(4), 985-998); diabetes (including insulin-resistant diabetes or diabetic conditions mediated by insulin sensitivity or secretion) (Razavi, R. et al., Cell 2006, 127(6), 1097-1099; Akiba, Y. et al., Biochem. Biophy. Res. Commun. 2004, 321(1), 219-225).
Acidosis is a well-established feature of cerebral ischaemia. Tissue pH may fall to 6 or lower, sufficient to activate TRPV1 channels expressed in the CNS. TRPV1 antagonists therefore may be useful in the treatment of disorders associated with reduced blood flow to the CNS or CNS hypoxia, such as head trauma, spinal injury, thromboembolic or hemorrhagic stroke, transient ischaemic attacks, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, Alzheimer's disease, and Huntington's Disease.
Certain thiazole carboxamides have been described as vanilloid receptor modulators (Xi et al., Bioorg. Med. Chem. Lett. 2005, 15, 5211-5217; U.S. Pat. Appl. Publ. 2004/157845). Certain thiazolopyrimidines have been described as CCR2b receptor antagonists (PCT Intl. Pat. Appl. Publ. WO 2005/117890), chemokine receptor antagonists (U.S. Pat. Appl. Publ. 2007/0142386; Baxter et al. Bioorg. Med. Chem. Lett. 2006, 26, 960-963), and inhibitors of ATP-protein kinase interactions (U.S. Pat. Appl. Publ. 2007/0185139). Certain thiazolopyrimidine compounds were described as TRPV1 modulators in U.S. patent application Ser. No. 11/824,202. Certain thiazolopyrimidine derivatives are disclosed as growth factor receptor tyrosine kinase inhibitors in Eur. Pat. Appl. EP 1731523 (Dec. 13, 2006). Condensed heterocyclic compounds are shown as macrophage migration inhibitory factor inhibitors in JP 2001097979. Certain fused pyrimidines are described as modulators of metabotropic receptors—subtype 2 in PCT Intl. Pat. Appl. Publ. WO 2006/030031. Bicyclic pyrimidinyl derivatives are disclosed as adenosine receptor binders in U.S. Pat. Appl. Publ. US 2003/139427 and U.S. Pat. Appl. Publ. US 2002/094974. Purine derivatives are described as nerve growth promoters in PCT Intl. Pat. Appl. Publ. WO 2006/130469. Various purine analogs are disclosed as heat shock protein 90 inhibitors in U.S. Pat. Appl. Publ. 2005/0049263. Purine analogs are also described as inhibitors of cyclin dependent kinases in U.S. Pat. Appl. Publ. 2003/191086.
There remains a desire for potent TRPV1 modulators with suitable pharmaceutical properties.